Robin K. Dore, MD

The United States preventive services task force (USPSTF) recently threw cold water on the use of calcium and vitamin D supplements to prevent fractures in adults, either finding inadequate evidence to make a recommendation or recommending against supplementation, depending on the population and the doses used.¹

Complicating this issue, several recent studies have raised concern about the long-term cardiovascular risk of calcium supplementation.

With so many people taking calcium supplements, how do we put this into context for our patients? I believe that we need to consider the whole person when discussing these supplements, as there are data that they also help reduce the risk of falls, cancer, and even overall mortality rates.

THE USPSTF’S METHODS

The USPSTF bases its recommendations on explicit criteria² developed by its Evidence-based Practice Center, which is under contract to the US Agency for Healthcare Research and Quality to conduct systematic reviews of the evidence on specific topics in clinical prevention. The USPSTF grades the strength of the evidence for the effectiveness of specific clinical preventive services as:

• A (strongly recommended)
• B (recommended)
• C (no recommendation)
• D (recommended against)
• I (insufficient evidence to make a recommendation for or against).

USPSTF recommendations consider the evidence of both benefit and harm of the intervention but do not include the cost of the intervention in the assessment.³

THE USPSTF’S GRADES ON CALCIUM AND VITAMIN D SUPPLEMENTATION

The USPSTF made the following recommendations in February 2013 about the use of calcium and vitamin D supplementation:

• For primary prevention of fractures in premenopausal women and men: grade I (current evidence is insufficient to assess the balance of the benefits and harms)
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses greater than 400 IU of vitamin D and greater than 1,000 mg of calcium: also grade I
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses of 400 IU or less of vitamin D and 1,000 mg or less of calcium: grade D (the USPSTF recommends against it, as these doses increase the incidence of renal stones and there is “adequate” evidence that these doses have no effect on the incidence of fractures).

WHAT THE USPSTF DID NOT DISCUSS

These recommendations do not apply to everybody. Rather, the document discusses “the effectiveness of specific clinical preventive services for patients without related signs or symptoms,”¹ and states that the recommendations do not pertain to patients with osteoporosis or vitamin D deficiency or those who have had fractures.

Also, the document does not discuss the use of calcium supplementation by itself in fracture prevention. nor does it discuss possible benefits of calcium and vitamin D other than fracture prevention, such as reducing the risk of falls, cancer, or death. Further, the document states that “appropriate intake” of vitamin D and calcium is “essential to overall health”¹ but does not state the amount that is considered appropriate.

The document does refer the reader to other USPSTF recommendations concerning screening for osteoporosis in women age 65 and older and in younger women who demonstrate the fracture risk of a 65-year-old woman,⁴ as well as to its recommendation for vitamin D supplementation to prevent falls in community-dwelling adults age 65 and older who are at higher risk of falls.⁵

Not included: A new meta-analysis

The USPSTF document also notes that after their review was completed, another metaanalysis concluded that fracture risk may be reduced by taking vitamin D in doses of 800 IU or higher.⁶

In that study, Bischoff-Ferrari et al⁶ performed a pooled analysis of vitamin D dose requirements for fracture prevention from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation taken either daily or at weekly or 4-month intervals with or without calcium, compared with placebo or calcium alone in people age 65 and older. The primary end points were the incidence of hip fracture and any nonvertebral fracture according to Cox regression analysis, with adjustment for age, sex, community or institutional dwelling, and study. The aim was to evaluate actual vitamin D intake rather than the assigned dosage groups in the trials.

On the basis of actual vitamin D intake, the incidence of hip fracture was significantly (30%) lower in people with the highest actual intake (792–2,000 IU per day) than in controls. There was no reduction in the risk of hip fracture at any actual intake levels lower than 792 IU per day. Using this same analytic technique, the reduction in the incidence of nonvertebral fracture at the highest actual intake level was 16%.

Why were their findings different than those of the USPSTF? The authors hypothesized that some previous high-quality trials of vitamin D supplementation either showed no benefit because the participants were noncompliant and thus took less than the intended dose of vitamin D, or showed an unexpected benefit because the participants actually took more vitamin D than was specified in the study.

The USPSTF recommendations did not include studies of vitamin D without calcium, whereas Bischoff-Ferrari et al did, which could also explain some of the differences in the findings, as not all of the studies included in the two documents were the same. Several previous meta-analyses suggested that the dose of vitamin D was irrelevant when vitamin D was combined with calcium.

The data from Bischoff-Ferrari et al suggested that at the highest actual intake level of vitamin D, a smaller amount of calcium supplementation (< 1,000 mg daily) may be more beneficial in reducing fracture risk than a larger amount (≥ 1,000 mg daily). This is important, given the current level of concern initially raised by Bolland et al⁷ and others about the possible risks of higher doses of calcium supplements increasing cardiovascular risk. (More on this below.)

WHAT OTHER ORGANIZATIONS SAY

Both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research suggest following the 2010 recommendations of the Institute of Medicine⁸ on calcium and vitamin D instead of those of the USPSTF, as the former address the overall health benefits of calcium and vitamin D in healthy individuals rather than only fracture prevention.

Neither the Institute of Medicine nor the USPSTF, however, addresses vitamin D requirements of people at high risk, such as those with vitamin D deficiency due to very little sun exposure, dark skin, problems absorbing dietary fat, or medications that interfere with vitamin D absorption, or those with osteoporosis.

The Institute of Medicine suggests that, for healthy adults under age 71, an adequate vitamin D intake is 600 IU daily, and for healthy adults age 71 and older it is 800 IU daily. They state that the safe upper limit for daily intake of vitamin D is 4,000 IU. As for adequate calcium intake, the daily recommendation is 1,200 mg for women ages 50 through 70, and 1,200 mg for all adults age 71 and older. As I have already discussed, the Institute of Medicine recommendations are based on the overall health benefits of calcium and vitamin D rather than solely on fracture prevention. Monitoring of vitamin D levels is not recommended unless the patient has osteoporosis or is at risk for vitamin D deficiency.

Risks of calcium supplementation

Much has been written recently about the risks of calcium supplementation.

This concern was first raised in 2008 by Bolland et al⁷ in a post hoc analysis of data collected to evaluate the effect of calcium supplements on bone density and fracture.⁷ More myocardial infarctions occurred in the calcium supplement group than in the placebo group, but the difference was not statistically significant, and the events occurred only in those who took more than 1,000 mg of calcium daily.

The same group reanalyzed data from the Women’s Health Initiative and found a 24% higher risk of myocardial infarction in women who took calcium with or without vitamin D, but only in those women assigned to take calcium supplementation who had not taken calcium supplements before the study began.⁹

More recently, Xiao et al¹⁰ evaluated the effect of both dietary and supplemental calcium on cardiovascular disease mortality rates.¹⁰ This was a prospective study of 388,229 men and women who participated in the National Institutes of Health-American Association of Retired Persons Diet and Heart Study. Supplemental calcium intake was associated with an elevated risk of cardiovascular disease in men, but not in women. Dietary calcium intake was unrelated to cardiovascular death.

The latest study to address this issue was from the Swedish Mammography Cohort, a population-based cohort that included 61,433 women born between 1914 and 1948, with a mean follow-up of 19 years.¹¹ Diet was evaluated by food frequency questionnaires. A daily dietary intake of calcium below 600 mg was associated with higher risks of all-cause mortality, cardiovascular disease, ischemic heart disease, and stroke. However, compared with women whose daily calcium intake was between 600 and 999 mg, a dietary intake of more than 1,400 mg/day was associated with a higher death rate, with a hazard ratio for all-cause mortality of 1.40, cardiovascular disease 1.49, and ischemic heart disease 2.14.

Unfortunately, none of these studies were designed to assess the risk of cardiovascular disease related to calcium supplementation. Like the USPSTF, both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research state that this type of study is needed to clarify both the benefit and risk of calcium supplementation.

Until these data are available, the American Society of Bone and Mineral Research has advised doctors and their patients “to discuss the best strategy for each individual patient, putting supplements as the last resort for healthier adults if they cannot reach recommended levels through the intake of calcium and vitamin rich foods.” For adults who cannot tolerate dairy products, calcium can be obtained from calcium-supplemented foods such as orange juice and Jello and from nondairy sources such as leafy green vegetables, almonds, garbanzo beans, tofu, and eggs.¹²

The National Osteoporosis Foundation suggests following the Institute of Medicine recommendations for adequate calcium and vitamin D rather than the USPSTF recommendations, most likely because the former are based on the overall health benefits of calcium and vitamin D rather than fracture prevention only. However, it reminds us that the Institute of Medicine recommendations do not apply to patients who are at the highest risk of fracture, ie, those with osteoporosis and vitamin D deficiency.

TAKE-HOME POINTS

• All medications, including those available over the counter, have benefits and risks.
• Even the USPSTF states that for a healthy lifestyle, the diet should contain adequate calcium and vitamin D intake.
• When following guidelines, practitioners should be certain that the guidelines pertain to the population they are treating—for example, not to apply the Institute of Medicine recommendations to a woman with a hip fracture, but that a healthy premenopausal woman who is taking calcium supplements should be advised to stop the supplements and focus on dietary sources of calcium.
• Only if individuals cannot obtain the recommended amount of calcium in their diet is it advisable for them to take a calcium supplement.

My recommendations

Based on the information summarized above, I recommend that my patients obtain as much calcium as possible from their diet—between 600 and 1,200 mg daily—and to take a calcium supplement only if they cannot obtain that amount of calcium in the diet. However, 24-hour calcium excretion is not recommended as a marker of calcium intake.

I also advise my patients to take a vitamin D supplement, per the Institute of Medicine report for overall good health. The USPSTF recommendations concerning vitamin D and calcium address only fracture prevention. As I am responsible for the overall health of my patients, not just fracture prevention, I choose to follow the National Osteoporosis Foundation and Institute of Medicine recommendations, not those of the USPSTF.

The United States preventive services task force (USPSTF) recently threw cold water on the use of calcium and vitamin D supplements to prevent fractures in adults, either finding inadequate evidence to make a recommendation or recommending against supplementation, depending on the population and the doses used.¹

Complicating this issue, several recent studies have raised concern about the long-term cardiovascular risk of calcium supplementation.

With so many people taking calcium supplements, how do we put this into context for our patients? I believe that we need to consider the whole person when discussing these supplements, as there are data that they also help reduce the risk of falls, cancer, and even overall mortality rates.

THE USPSTF’S METHODS

The USPSTF bases its recommendations on explicit criteria² developed by its Evidence-based Practice Center, which is under contract to the US Agency for Healthcare Research and Quality to conduct systematic reviews of the evidence on specific topics in clinical prevention. The USPSTF grades the strength of the evidence for the effectiveness of specific clinical preventive services as:

• A (strongly recommended)
• B (recommended)
• C (no recommendation)
• D (recommended against)
• I (insufficient evidence to make a recommendation for or against).

USPSTF recommendations consider the evidence of both benefit and harm of the intervention but do not include the cost of the intervention in the assessment.³

THE USPSTF’S GRADES ON CALCIUM AND VITAMIN D SUPPLEMENTATION

The USPSTF made the following recommendations in February 2013 about the use of calcium and vitamin D supplementation:

• For primary prevention of fractures in premenopausal women and men: grade I (current evidence is insufficient to assess the balance of the benefits and harms)
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses greater than 400 IU of vitamin D and greater than 1,000 mg of calcium: also grade I
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses of 400 IU or less of vitamin D and 1,000 mg or less of calcium: grade D (the USPSTF recommends against it, as these doses increase the incidence of renal stones and there is “adequate” evidence that these doses have no effect on the incidence of fractures).

WHAT THE USPSTF DID NOT DISCUSS

These recommendations do not apply to everybody. Rather, the document discusses “the effectiveness of specific clinical preventive services for patients without related signs or symptoms,”¹ and states that the recommendations do not pertain to patients with osteoporosis or vitamin D deficiency or those who have had fractures.

Also, the document does not discuss the use of calcium supplementation by itself in fracture prevention. nor does it discuss possible benefits of calcium and vitamin D other than fracture prevention, such as reducing the risk of falls, cancer, or death. Further, the document states that “appropriate intake” of vitamin D and calcium is “essential to overall health”¹ but does not state the amount that is considered appropriate.

The document does refer the reader to other USPSTF recommendations concerning screening for osteoporosis in women age 65 and older and in younger women who demonstrate the fracture risk of a 65-year-old woman,⁴ as well as to its recommendation for vitamin D supplementation to prevent falls in community-dwelling adults age 65 and older who are at higher risk of falls.⁵

Not included: A new meta-analysis

The USPSTF document also notes that after their review was completed, another metaanalysis concluded that fracture risk may be reduced by taking vitamin D in doses of 800 IU or higher.⁶

In that study, Bischoff-Ferrari et al⁶ performed a pooled analysis of vitamin D dose requirements for fracture prevention from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation taken either daily or at weekly or 4-month intervals with or without calcium, compared with placebo or calcium alone in people age 65 and older. The primary end points were the incidence of hip fracture and any nonvertebral fracture according to Cox regression analysis, with adjustment for age, sex, community or institutional dwelling, and study. The aim was to evaluate actual vitamin D intake rather than the assigned dosage groups in the trials.

On the basis of actual vitamin D intake, the incidence of hip fracture was significantly (30%) lower in people with the highest actual intake (792–2,000 IU per day) than in controls. There was no reduction in the risk of hip fracture at any actual intake levels lower than 792 IU per day. Using this same analytic technique, the reduction in the incidence of nonvertebral fracture at the highest actual intake level was 16%.

Why were their findings different than those of the USPSTF? The authors hypothesized that some previous high-quality trials of vitamin D supplementation either showed no benefit because the participants were noncompliant and thus took less than the intended dose of vitamin D, or showed an unexpected benefit because the participants actually took more vitamin D than was specified in the study.

The USPSTF recommendations did not include studies of vitamin D without calcium, whereas Bischoff-Ferrari et al did, which could also explain some of the differences in the findings, as not all of the studies included in the two documents were the same. Several previous meta-analyses suggested that the dose of vitamin D was irrelevant when vitamin D was combined with calcium.

The data from Bischoff-Ferrari et al suggested that at the highest actual intake level of vitamin D, a smaller amount of calcium supplementation (< 1,000 mg daily) may be more beneficial in reducing fracture risk than a larger amount (≥ 1,000 mg daily). This is important, given the current level of concern initially raised by Bolland et al⁷ and others about the possible risks of higher doses of calcium supplements increasing cardiovascular risk. (More on this below.)

WHAT OTHER ORGANIZATIONS SAY

Both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research suggest following the 2010 recommendations of the Institute of Medicine⁸ on calcium and vitamin D instead of those of the USPSTF, as the former address the overall health benefits of calcium and vitamin D in healthy individuals rather than only fracture prevention.

Neither the Institute of Medicine nor the USPSTF, however, addresses vitamin D requirements of people at high risk, such as those with vitamin D deficiency due to very little sun exposure, dark skin, problems absorbing dietary fat, or medications that interfere with vitamin D absorption, or those with osteoporosis.

The Institute of Medicine suggests that, for healthy adults under age 71, an adequate vitamin D intake is 600 IU daily, and for healthy adults age 71 and older it is 800 IU daily. They state that the safe upper limit for daily intake of vitamin D is 4,000 IU. As for adequate calcium intake, the daily recommendation is 1,200 mg for women ages 50 through 70, and 1,200 mg for all adults age 71 and older. As I have already discussed, the Institute of Medicine recommendations are based on the overall health benefits of calcium and vitamin D rather than solely on fracture prevention. Monitoring of vitamin D levels is not recommended unless the patient has osteoporosis or is at risk for vitamin D deficiency.

Risks of calcium supplementation

Much has been written recently about the risks of calcium supplementation.

This concern was first raised in 2008 by Bolland et al⁷ in a post hoc analysis of data collected to evaluate the effect of calcium supplements on bone density and fracture.⁷ More myocardial infarctions occurred in the calcium supplement group than in the placebo group, but the difference was not statistically significant, and the events occurred only in those who took more than 1,000 mg of calcium daily.

The same group reanalyzed data from the Women’s Health Initiative and found a 24% higher risk of myocardial infarction in women who took calcium with or without vitamin D, but only in those women assigned to take calcium supplementation who had not taken calcium supplements before the study began.⁹

More recently, Xiao et al¹⁰ evaluated the effect of both dietary and supplemental calcium on cardiovascular disease mortality rates.¹⁰ This was a prospective study of 388,229 men and women who participated in the National Institutes of Health-American Association of Retired Persons Diet and Heart Study. Supplemental calcium intake was associated with an elevated risk of cardiovascular disease in men, but not in women. Dietary calcium intake was unrelated to cardiovascular death.

The latest study to address this issue was from the Swedish Mammography Cohort, a population-based cohort that included 61,433 women born between 1914 and 1948, with a mean follow-up of 19 years.¹¹ Diet was evaluated by food frequency questionnaires. A daily dietary intake of calcium below 600 mg was associated with higher risks of all-cause mortality, cardiovascular disease, ischemic heart disease, and stroke. However, compared with women whose daily calcium intake was between 600 and 999 mg, a dietary intake of more than 1,400 mg/day was associated with a higher death rate, with a hazard ratio for all-cause mortality of 1.40, cardiovascular disease 1.49, and ischemic heart disease 2.14.

Unfortunately, none of these studies were designed to assess the risk of cardiovascular disease related to calcium supplementation. Like the USPSTF, both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research state that this type of study is needed to clarify both the benefit and risk of calcium supplementation.

Until these data are available, the American Society of Bone and Mineral Research has advised doctors and their patients “to discuss the best strategy for each individual patient, putting supplements as the last resort for healthier adults if they cannot reach recommended levels through the intake of calcium and vitamin rich foods.” For adults who cannot tolerate dairy products, calcium can be obtained from calcium-supplemented foods such as orange juice and Jello and from nondairy sources such as leafy green vegetables, almonds, garbanzo beans, tofu, and eggs.¹²

The National Osteoporosis Foundation suggests following the Institute of Medicine recommendations for adequate calcium and vitamin D rather than the USPSTF recommendations, most likely because the former are based on the overall health benefits of calcium and vitamin D rather than fracture prevention only. However, it reminds us that the Institute of Medicine recommendations do not apply to patients who are at the highest risk of fracture, ie, those with osteoporosis and vitamin D deficiency.

TAKE-HOME POINTS

• All medications, including those available over the counter, have benefits and risks.
• Even the USPSTF states that for a healthy lifestyle, the diet should contain adequate calcium and vitamin D intake.
• When following guidelines, practitioners should be certain that the guidelines pertain to the population they are treating—for example, not to apply the Institute of Medicine recommendations to a woman with a hip fracture, but that a healthy premenopausal woman who is taking calcium supplements should be advised to stop the supplements and focus on dietary sources of calcium.
• Only if individuals cannot obtain the recommended amount of calcium in their diet is it advisable for them to take a calcium supplement.

My recommendations

Based on the information summarized above, I recommend that my patients obtain as much calcium as possible from their diet—between 600 and 1,200 mg daily—and to take a calcium supplement only if they cannot obtain that amount of calcium in the diet. However, 24-hour calcium excretion is not recommended as a marker of calcium intake.

I also advise my patients to take a vitamin D supplement, per the Institute of Medicine report for overall good health. The USPSTF recommendations concerning vitamin D and calcium address only fracture prevention. As I am responsible for the overall health of my patients, not just fracture prevention, I choose to follow the National Osteoporosis Foundation and Institute of Medicine recommendations, not those of the USPSTF.

The United States preventive services task force (USPSTF) recently threw cold water on the use of calcium and vitamin D supplements to prevent fractures in adults, either finding inadequate evidence to make a recommendation or recommending against supplementation, depending on the population and the doses used.¹

Complicating this issue, several recent studies have raised concern about the long-term cardiovascular risk of calcium supplementation.

With so many people taking calcium supplements, how do we put this into context for our patients? I believe that we need to consider the whole person when discussing these supplements, as there are data that they also help reduce the risk of falls, cancer, and even overall mortality rates.

THE USPSTF’S METHODS

The USPSTF bases its recommendations on explicit criteria² developed by its Evidence-based Practice Center, which is under contract to the US Agency for Healthcare Research and Quality to conduct systematic reviews of the evidence on specific topics in clinical prevention. The USPSTF grades the strength of the evidence for the effectiveness of specific clinical preventive services as:

• A (strongly recommended)
• B (recommended)
• C (no recommendation)
• D (recommended against)
• I (insufficient evidence to make a recommendation for or against).

USPSTF recommendations consider the evidence of both benefit and harm of the intervention but do not include the cost of the intervention in the assessment.³

THE USPSTF’S GRADES ON CALCIUM AND VITAMIN D SUPPLEMENTATION

The USPSTF made the following recommendations in February 2013 about the use of calcium and vitamin D supplementation:

• For primary prevention of fractures in premenopausal women and men: grade I (current evidence is insufficient to assess the balance of the benefits and harms)
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses greater than 400 IU of vitamin D and greater than 1,000 mg of calcium: also grade I
• For primary prevention of fractures in noninstitutionalized postmenopausal women, in daily doses of 400 IU or less of vitamin D and 1,000 mg or less of calcium: grade D (the USPSTF recommends against it, as these doses increase the incidence of renal stones and there is “adequate” evidence that these doses have no effect on the incidence of fractures).

WHAT THE USPSTF DID NOT DISCUSS

These recommendations do not apply to everybody. Rather, the document discusses “the effectiveness of specific clinical preventive services for patients without related signs or symptoms,”¹ and states that the recommendations do not pertain to patients with osteoporosis or vitamin D deficiency or those who have had fractures.

Also, the document does not discuss the use of calcium supplementation by itself in fracture prevention. nor does it discuss possible benefits of calcium and vitamin D other than fracture prevention, such as reducing the risk of falls, cancer, or death. Further, the document states that “appropriate intake” of vitamin D and calcium is “essential to overall health”¹ but does not state the amount that is considered appropriate.

The document does refer the reader to other USPSTF recommendations concerning screening for osteoporosis in women age 65 and older and in younger women who demonstrate the fracture risk of a 65-year-old woman,⁴ as well as to its recommendation for vitamin D supplementation to prevent falls in community-dwelling adults age 65 and older who are at higher risk of falls.⁵

Not included: A new meta-analysis

The USPSTF document also notes that after their review was completed, another metaanalysis concluded that fracture risk may be reduced by taking vitamin D in doses of 800 IU or higher.⁶

In that study, Bischoff-Ferrari et al⁶ performed a pooled analysis of vitamin D dose requirements for fracture prevention from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation taken either daily or at weekly or 4-month intervals with or without calcium, compared with placebo or calcium alone in people age 65 and older. The primary end points were the incidence of hip fracture and any nonvertebral fracture according to Cox regression analysis, with adjustment for age, sex, community or institutional dwelling, and study. The aim was to evaluate actual vitamin D intake rather than the assigned dosage groups in the trials.

On the basis of actual vitamin D intake, the incidence of hip fracture was significantly (30%) lower in people with the highest actual intake (792–2,000 IU per day) than in controls. There was no reduction in the risk of hip fracture at any actual intake levels lower than 792 IU per day. Using this same analytic technique, the reduction in the incidence of nonvertebral fracture at the highest actual intake level was 16%.

Why were their findings different than those of the USPSTF? The authors hypothesized that some previous high-quality trials of vitamin D supplementation either showed no benefit because the participants were noncompliant and thus took less than the intended dose of vitamin D, or showed an unexpected benefit because the participants actually took more vitamin D than was specified in the study.

The USPSTF recommendations did not include studies of vitamin D without calcium, whereas Bischoff-Ferrari et al did, which could also explain some of the differences in the findings, as not all of the studies included in the two documents were the same. Several previous meta-analyses suggested that the dose of vitamin D was irrelevant when vitamin D was combined with calcium.

The data from Bischoff-Ferrari et al suggested that at the highest actual intake level of vitamin D, a smaller amount of calcium supplementation (< 1,000 mg daily) may be more beneficial in reducing fracture risk than a larger amount (≥ 1,000 mg daily). This is important, given the current level of concern initially raised by Bolland et al⁷ and others about the possible risks of higher doses of calcium supplements increasing cardiovascular risk. (More on this below.)

WHAT OTHER ORGANIZATIONS SAY

Both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research suggest following the 2010 recommendations of the Institute of Medicine⁸ on calcium and vitamin D instead of those of the USPSTF, as the former address the overall health benefits of calcium and vitamin D in healthy individuals rather than only fracture prevention.

Neither the Institute of Medicine nor the USPSTF, however, addresses vitamin D requirements of people at high risk, such as those with vitamin D deficiency due to very little sun exposure, dark skin, problems absorbing dietary fat, or medications that interfere with vitamin D absorption, or those with osteoporosis.

The Institute of Medicine suggests that, for healthy adults under age 71, an adequate vitamin D intake is 600 IU daily, and for healthy adults age 71 and older it is 800 IU daily. They state that the safe upper limit for daily intake of vitamin D is 4,000 IU. As for adequate calcium intake, the daily recommendation is 1,200 mg for women ages 50 through 70, and 1,200 mg for all adults age 71 and older. As I have already discussed, the Institute of Medicine recommendations are based on the overall health benefits of calcium and vitamin D rather than solely on fracture prevention. Monitoring of vitamin D levels is not recommended unless the patient has osteoporosis or is at risk for vitamin D deficiency.

Risks of calcium supplementation

Much has been written recently about the risks of calcium supplementation.

This concern was first raised in 2008 by Bolland et al⁷ in a post hoc analysis of data collected to evaluate the effect of calcium supplements on bone density and fracture.⁷ More myocardial infarctions occurred in the calcium supplement group than in the placebo group, but the difference was not statistically significant, and the events occurred only in those who took more than 1,000 mg of calcium daily.

The same group reanalyzed data from the Women’s Health Initiative and found a 24% higher risk of myocardial infarction in women who took calcium with or without vitamin D, but only in those women assigned to take calcium supplementation who had not taken calcium supplements before the study began.⁹

More recently, Xiao et al¹⁰ evaluated the effect of both dietary and supplemental calcium on cardiovascular disease mortality rates.¹⁰ This was a prospective study of 388,229 men and women who participated in the National Institutes of Health-American Association of Retired Persons Diet and Heart Study. Supplemental calcium intake was associated with an elevated risk of cardiovascular disease in men, but not in women. Dietary calcium intake was unrelated to cardiovascular death.

The latest study to address this issue was from the Swedish Mammography Cohort, a population-based cohort that included 61,433 women born between 1914 and 1948, with a mean follow-up of 19 years.¹¹ Diet was evaluated by food frequency questionnaires. A daily dietary intake of calcium below 600 mg was associated with higher risks of all-cause mortality, cardiovascular disease, ischemic heart disease, and stroke. However, compared with women whose daily calcium intake was between 600 and 999 mg, a dietary intake of more than 1,400 mg/day was associated with a higher death rate, with a hazard ratio for all-cause mortality of 1.40, cardiovascular disease 1.49, and ischemic heart disease 2.14.

Unfortunately, none of these studies were designed to assess the risk of cardiovascular disease related to calcium supplementation. Like the USPSTF, both the National Osteoporosis Foundation and the American Society of Bone and Mineral Research state that this type of study is needed to clarify both the benefit and risk of calcium supplementation.

Until these data are available, the American Society of Bone and Mineral Research has advised doctors and their patients “to discuss the best strategy for each individual patient, putting supplements as the last resort for healthier adults if they cannot reach recommended levels through the intake of calcium and vitamin rich foods.” For adults who cannot tolerate dairy products, calcium can be obtained from calcium-supplemented foods such as orange juice and Jello and from nondairy sources such as leafy green vegetables, almonds, garbanzo beans, tofu, and eggs.¹²

The National Osteoporosis Foundation suggests following the Institute of Medicine recommendations for adequate calcium and vitamin D rather than the USPSTF recommendations, most likely because the former are based on the overall health benefits of calcium and vitamin D rather than fracture prevention only. However, it reminds us that the Institute of Medicine recommendations do not apply to patients who are at the highest risk of fracture, ie, those with osteoporosis and vitamin D deficiency.

TAKE-HOME POINTS

• All medications, including those available over the counter, have benefits and risks.
• Even the USPSTF states that for a healthy lifestyle, the diet should contain adequate calcium and vitamin D intake.
• When following guidelines, practitioners should be certain that the guidelines pertain to the population they are treating—for example, not to apply the Institute of Medicine recommendations to a woman with a hip fracture, but that a healthy premenopausal woman who is taking calcium supplements should be advised to stop the supplements and focus on dietary sources of calcium.
• Only if individuals cannot obtain the recommended amount of calcium in their diet is it advisable for them to take a calcium supplement.

My recommendations

Based on the information summarized above, I recommend that my patients obtain as much calcium as possible from their diet—between 600 and 1,200 mg daily—and to take a calcium supplement only if they cannot obtain that amount of calcium in the diet. However, 24-hour calcium excretion is not recommended as a marker of calcium intake.

I also advise my patients to take a vitamin D supplement, per the Institute of Medicine report for overall good health. The USPSTF recommendations concerning vitamin D and calcium address only fracture prevention. As I am responsible for the overall health of my patients, not just fracture prevention, I choose to follow the National Osteoporosis Foundation and Institute of Medicine recommendations, not those of the USPSTF.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.